Neuronal Nicotinic Acetylcholine Receptors (nAChRs) are an abundantly expressed and molecularly diverse family of cation channel proteins that mediated key physiological functions in the brain. Learning, memory, and nociception have been linked to cholinergic activity. Nicotine addiction depends on nAChR function and important human diseases (epilepsy, schizophrenia, Alzheimer's) have been linked to defects in cholinergic signaling. Neuronal nAChR subunits associate in a variety of combinations to produce pentameric receptors that facilitate cation transport upon binding to the neurotransmitter acetylcholine. Although at least 15 different types of vertebrate nAChR subunits have yet to be identified. This prediction is underscored by the recent discovery of at least 40 distinct nAChR subunit genes in the genome of a much smaller and simpler organism, the nematode, C. elegans. The goal of this project is to define the physiological and behavioral roles of a subset of these nAChR proteins in C. elegans motor neurons. At least five different nAChR subunit genes ("MnAChRs") are expressed in C. elegans motor neurons. Although nAChR expression has also been detected in the vertebrate spinal cord, the roles of nAChRs in mammalian motor neuron function are largely unknown. The well-defined neuroanatomy and relative simplicity of the C. elegans motor neuron circuit will facilitate our effort to detect motor neuron-specific expression and to define the intracellular localization of these nAChR subunits. In addition, we will exploit the powerful genetics of C. elegans to detect functional interactions between the nAChR genes and to perform genetic screens that can reveal new components of these signaling pathways. Ultimately, our approach should reveal functionally important and evolutionarily conserved proteins that also mediate cholinergic signaling in the human brain.